Practical Synthesis of -oxo benzo[d]thiazol sulfones: Scope and Limitations

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1 Electronic Supplementary Information Practical Synthesis of -oxo benzo[d]thiazol sulfones: Scope and Limitations Jiří Pospíšil,* Raphaël Robiette, Hitoshi Sato and Kevin Debrus Institute of Condensed Matter and Nanosciences Molecules, Solids and Reactivity (IMCN/MOST), Université catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium Table of Contents Electronic Supplementary Information... 1 Experimental procedures... 3 Sulfone synthesis (5) (methylthio)benzo[d]thiazole (5a) (heptylsulfonyl)benzo[d]thiazole (5b) (benzylsulfonyl)benzo[d]thiazole (5c)... 5 Starting from alcohol and BT-SH or PT-SH (tricosanylsulfonyl)benzo[d]thiazole (5d) (hex-3-yn-1-ylsulfonyl)benzo[d]thiazole (5e) (hex-5-en-1-ylsulfonyl)benzo[d]thiazole (5f) ((4-((tert-butyldiphenylsilyl)oxy)butyl)sulfonyl)benzo[d]thiazole (5g)... 7 Self-condensation of sulfone 5a ((benzo[d]thiazol-2-ylmethyl)sulfonyl)benzo[d]thiazole (7) Heterosulfonyl ketones (4) and esters (11) (benzo[d]thiazol-2-ylsulfonyl)-1-phenylethanone (4a) (benzo[d]thiazol-2-ylsulfonyl)propan-2-one (4b) (benzo[d]thiazol-2-ylsulfonyl)-1-cyclohexyloctan-1-one (4c) (benzo[d]thiazol-2-ylsulfonyl)-1-mesityloctan-1-one (4d) S-1

2 3-(benzo[d]thiazol-2-ylsulfonyl)-1-phenoxynonan-2-one (4e) ethyl 3-(benzo[d]thiazol-2-ylsulfonyl)-2-oxononanoate (4f) (benzo[d]thiazol-2-ylsulfonyl)-1-chloroundecan-4-one (4g) (benzo[d]thiazol-2-ylsulfonyl)-1-cyclohexylethanoe (4h) methyl 2-(benzo[d]thiazol-2-ylsulfonyl)acetate (11a) allyl 2-(benzo[d]thiazol-2-ylsulfonyl)acetate (11b) tert-butyl 2-(benzo[d]thiazol-2-ylsulfonyl)acetate (11c) methyl 2-(benzo[d]thiazol-2-ylsulfonyl)-2-phenylacetate (11d) tert-butyl 2-(benzo[d]thiazol-2-ylsulfonyl)-2-phenylacetate (11e) methyl 2-(benzo[d]thiazol-2-ylsulfonyl)-2-lignocerate (11f) methyl 2-(benzo[d]thiazol-2-ylsulfonyl)hept-5-ynoate (11g) allyl 2-(benzo[d]thiazol-2-ylsulfonyl)hept-5-ynoate (11h) methyl 2-(benzo[d]thiazol-2-ylsulfonyl)hept-6-enoate (11i) methyl 2-(benzo[d]thiazol-2-ylsulfonyl)-5-((tert-butyldiphenylsilyl)oxy)pentanoate (11j) allyl 2-(benzo[d]thiazol-2-ylsulfonyl)octanoate (11k) S-ethyl 2-(benzo[d]thiazol-2-ylsulfonyl)ethanethioate (11l) (benzo[d]thiazol-2-ylsulfonyl)-N,N-diethylacetamide (11m) Synthesis of 2-(((phenylsulfonyl)methyl)sulfonyl)benzo[d]thiazole (12b) ((Iodomethyl)sulfonyl)benzene (S-6) (((phenylsulfonyl)methyl)thio)benzo[d]thiazole (S-7) (((phenylsulfonyl)methyl)sulfonyl)benzo[d]thiazole (12b) Computations Computational details Conformational analysis Litterature S-2

3 Experimental procedures Sulfone synthesis (5) 2-(methylthio)benzo[d]thiazole (5a) Sulfide S-1 synthesis: A solution of BTSH (10.0 g, 59.8 mmol, 1.0 equiv) in THF (240 ml, 0.25M) was cooled to 0 C and NaH (60% in min. oil) (2.63 g, 65.8 mmol, 1.1 equiv) was added portionwise within 10 min. The resulting solution was stirred at 0 C for 30 min, before methyl iodide (4.5 ml, 71.8 mmol, 1.2 equiv) was added dropwise. The cooling bath was removed and the resulting mixture was allowed to warm to rt and stirred for a further 8h. Saturated aqueous NH 4 Cl (100 ml) was added and resulting layers were separated. The aqueous layer was extracted with EtOAc (3x250 ml) and the combined organic layers were washed with brine (50 ml), dried over MgSO 4, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:etoac = 10:1->4:1) yielding the desired sulfide as a white solid (10.5 g, 99 % yield). TLC (petroleum ether:etoac = 4:1) Mp = C, lit C; 1 H-NMR (300 MHz, CDCl 3 ): = 2.81 (s, 3H, H-1), 7.30 (td, J = 7.6, 1.2 Hz, 1 H), 7.43 (td, J = 8.3, 1.2 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 16.1 (C-1), 121.1, 121.5, 124.2, 126.2, 135.3, 153.5, (C-2); IR (film = 3062, 2925, 2851, 1462, 1429, 1311, 1240, 1082, 1007, 964, 908, 756, 727, 675. Sulfone 5a: A solution of sulfide (10.0 g, 55.2 mmol, 1.0 equiv) in EtOH (276 ml, 0.20M) was cooled to 0 C and Na 2 WO 4.2 H 2 O (1.82 g, 5.51 mmol, 0.1 equiv) was added. After 5 min at 0 C, 35% aqueous solution of H 2 O 2 (21.4 ml, 221 mmol, 4.0 equiv) was added dropwise. The resulting mixture was stirred at 0 C for 30 min, before the cooling bath was removed and the stirring continued at rt for a further 10h. Saturated aqueous Na 2 S 2 O 3 (100 ml) was added and resulting layers were separated. The aqueous layer was extracted with EtOAc (3x250 ml) and the combined organic layers were washed with brine (50 ml), dried over MgSO 4, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:etoac = 4:1->2:1->1:1) yielding the desired sulfone as yellowish crystals (9.88 g, 84 % yield). In some cases, if the reaction was stopped before a full sulfide and/or sulfoxide conversion, sulfoxide S-2 was isolated as a byproduct). S-3

4 TLC (petroleum ether:etoac = 2:1) Sulfone (5a) Mp = C, lit. 2 = C; 1 H-NMR (300 MHz, CDCl 3 ): = 3.40 (s, 3H, H-1), 7.60 (pd, J = 7.2, 1.4 Hz, 2H), 8.00 (dd, J = 7.2, 1.8 Hz, 1H), 8.19 (dd, J = 7.3, 1.7 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 42.6 (C-1), 122.5, 125.5, 127.8, 128.2, 136.7, 152.5, (C-3); IR (film): -1 = 3181, 3023, 3009, 2927, 1699, 1683, 1473, 1425, 1317, 1309, 1151, 1028, 956, 756, 690; MS (APCI), m/z (%): 214 (100) [M + +H], 183 (7), 251 (12), 136 (17); El. an. for C 8 H 7 NO 2 S 2, calc. C 45.23, H 3.31, N 6.57, S 30.07; found C 45.23, H 3.24, N 6.82, S Sulfoxide (S-2) Mp = C, lit. 3 = C; 1 H-NMR (300 MHz, CDCl 3 ): = 3.08 (d, J = 7.5 Hz, 1H, H-1), 7.48 (td, J = 7.9, 1.9 Hz, 1H), 7.55 (td, J = 8.1, 1.8 Hz, 1H), 7.99 (dd, J = 7.9, 1.4 Hz, 1H), 8.05 (dd, J = 8.1, 1.0 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 43.3 (C-1), 122.5, 124.1, 126.4, 127.1, 136.1, 153.9, (C-2); IR (film): -1 = 3062, 3000, 2915, 1649, 1558, 1475, 1427, 1338, 1315, 1236, 1153, 1086, 1059, 1003, 953, 758, 725; MS (APCI), m/z (%): 198 (100) [M + ], 183 (34), 180 (40), 151 (17), 136 (21); El. an. for C 8 H 7 NOS 2, calc. C 48.71, H 3.58, N 7.10; found C 49.03, H 3.68, N (heptylsulfonyl)benzo[d]thiazole (5b) Sulfide S-3 synthesis: A solution of BTSH (8.0 g, 47.8 mmol, 1.0 equiv) in THF (191 ml, 0.25M) was cooled to 0 C and NaH (60% in min. oil) (2.30 g, 57.4 mmol, 1.2 equiv) was added portionwise within 10 min. The resulting solution was stirred at 0 C for 30 min, before heptyl bromide (8.27 ml, 52.6 mmol, 1.1 equiv) was added dropwise. The cooling bath was removed and the resulting mixture was allowed to warm to rt and stirred for a further 8h. Saturated aqueous NH 4 Cl (100 ml) was added and resulting layers were separated. The aqueous layer was extracted with EtOAc (3x250 ml) and the combined organic layers were washed with brine (50 ml), dried over MgSO 4, filtered and the solvents were removed under reduced pressure. The crude sulfide was used in the next step without additional purification Sulfone 5b: A solution of crude sulfide S-3 in EtOH (214 ml, 0.20M) was cooled to 0 C and Na 2 WO 4.2 H 2 O (1.82 g, 5.51 mmol) was added. After 5 min at 0 C, 35% aqueous solution of H 2 O 2 (21.4 ml, 221 mmol) was added dropwise. The resulting mixture was stirred at 0 C for 30 min, before the cooling bath was removed and the stirring continued at rt for a further 10h. Saturated aqueous Na 2 S 2 O 3 (100 ml) was S-4

5 added and resulting layers were separated. The aqueous layer was extracted with EtOAc (3x250 ml) and the combined organic layers were washed with brine (50 ml), dried over MgSO 4, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:etoac = 20:1->10:1) yielding the desired sulfone 5b (13.4 g, 94 % yield). TLC (petroleum ether:etoac = 10:1) Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = 0.85 (t, J = 6.8 Hz, 3H, H-7), (m, 6H), 1.44 (dt, J = 14.6, 6.7 Hz, 2H, H-3), 1.88 (dt, J = 12.1, 7.6 Hz, 2H, H-2), 3.51 (dd, J = 9.1, 7.0 Hz, 2H, H-1), 7.63 (pd, J = 7.2, 1.8 Hz, 2H), 8.03 (dd, J = 7.2, 1.7 Hz, 1H), 8.23 (dd, J = 7.3, 1.5 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = (C-7), 22.43, 22.64, 28.37, 28.75, (C-2), (C-1), , , , , , , (C-8); IR (film): -1 = 3064, 2951, 2924, 2854, 1555, 1472, 1458, 1329, 1317, 1143, 1126, 1024, 912, 853, 762; MS (CI), m/z (%): 298 (100) [M + ], 299 (19), 250 (14), 234 (17), 183 (17), 136 (14); HRMS (CI), m/z: calc for C 14 H 20 NO 2 S 2, found (benzylsulfonyl)benzo[d]thiazole (5c) Sulfide S-5 synthesis: A solution of BTSH (6.51 g, 39 mmol, 1.0 equiv) in THF (195 ml, 0.20M) was cooled to 0 C and NaH (60% in min. oil) (1.86 g, 46.6 mmol, 1.2 equiv) was added portionwise within 10 min. The resulting solution was stirred at 0 C for 30 min, before benzyl bromide (5.33 ml, 46.6 mmol, 1.2 equiv) was added dropwise. The cooling bath was removed and the resulting mixture was allowed to warm to rt and stirred for a further 8h. Saturated aqueous NH 4 Cl (100 ml) was added and resulting layers were separated. The aqueous layer was extracted with EtOAc (3x250 ml) and the combined organic layers were washed with brine (50 ml), dried over MgSO 4, filtered and the solvents were removed under reduced pressure. The crude sulfide S-5 was used in the next step without further purification. Mp = C, lit. 4 = 39 C; 1 H-NMR (300 MHz, CDCl 3 ): = 4.61 (s, 2H, H-8), 7.30(m, 5H), 7, (m, 2H), 7.76 (d, J = 8.0 Hz, 1H),7.92 (d, J = 8.1 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 37.9 (C-8), 121.2, 121.8, 124.5, 126.3, 128.0, 128.9, 129.3, 135.5, 136.4, 153.4, (C-7); IR (film): -1 = 3060, 3028, 2922, 1600, 1560, 1495, 1454, 1425, 1310, 1275, 1238, 1126, 1074, 993, 916, 852, 754, 725, 698, 667. S-5

6 Sulfone 5c: A solution of crude sulfide S-5 in EtOH (200 ml, 0.20M) was cooled to 0 C and Na 2 WO 4.2 H 2 O (1.82 g, 5.51 mmol, 0.1 equiv) was added. After 5 min at 0 C, 35% aqueous solution of H 2 O 2 (15.2 ml, 156 mmol, 4.0 equiv) was added dropwise. The resulting mixture was stirred at 0 C for 30 min, before the cooling bath was removed. The reaction was stirred at rt for a further 10h. Saturated aqueous Na 2 S 2 O 3 (100 ml) was added and resulting layers were separated. The aqueous layer was extracted with EtOAc (3x250 ml) and the combined organic layers were washed with brine (50 ml), dried over MgSO 4, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:etoac = 10:1->2:1) yielding the desired sulfone 5c (8.94 g, 79 % yield). TLC (petroleum ether:etoac = 4:1) Mp = C, lit. 5 = 112 C; 1 H-NMR (300 MHz, CDCl 3 ): = 4.78 (s, 1H, H-2), (m, 5H), (m, 2H), 7.96 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 61.2 (C-2), 122.5, 125.7, 126.5, 127.9, 128.2, 129.1, 129.4, 131.3, 137.3, 152.8, (C-1); IR (film): -1 = 3063, 2982, 2922, 1553, 1470, 1456, 1331, 1198, 1153, 1071, 1026, 914, 874, 853, 762, 729, 696; MS (CI), m/z (%):290 (43) [M + ], 291 (9) [M + +1], 289 (23), 274 (22), 225 (37), 224 (100), 91 (97); HRMS (CI), m/z: calc for C 14 H 12 NO 2 S 2, found Starting from alcohol and BT-SH or PT-SH General procedure: A solution of BT-SH or PT-SH (1.2 mmol, 1.2 equiv), PPh 3 (1.2 mmol, 1.2 equiv) and alcohol (1.0 mmol, 1.0 equiv) in THF (10 ml, 0.1M) was cooled to 0 C and DEAD (1.2 mmol, 1.2 equiv) was added. The resulting solution was allowed to warm to rt and stirred for 5-8 h. The resulting solution was diluted with EtOH (25 ml), cooled to 0 C and Na 2 WO 4.2H 2 O (0.1 mmol, 0.1 equiv) in one portion. After 5 min at 0 C, an aqueous 35% solution of H 2 O 2 (10.0 mmol, 10 equiv) was added dropwise with a use of pipette Pasteur. The resulting yellowish solution was allowed to warm to rt and stirred at rt for 10h. Water (50 ml) was added and the whole mixture was extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (50 ml), dried over MgSO 4, filtered and the solvents were evaporated under reduced pressure. The residue was purified by flash chromatography on SiO 2 using the appropriate eluting system. 2-(tricosanylsulfonyl)benzo[d]thiazole (5d) S-6

7 Purification by flash chromatography (petroleum ether:etoac = 50:1 -> 10:1) gave sulfone 5d (459 mg, 89%). Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = 0.85 (t, J = 6.8 Hz, 3H, H-3), (m, 40H), 1.88 (dt, J = 12.1, 7.6 Hz, 2H, H-2), 3.51 (dd, J = 9.1, 7.0 Hz, 2H, H-1), 7.62 (pd, J = 7.2, 1.4 Hz, 2H), 8.03 (dd, J = 7.2, 1.7 Hz, 1H), 8.23 (dd, J = 7.3, 1.5 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 14.3 (C-6), 22.9, 26.4, 27.1, 29.2, 29.3, 29.6, 29.8, 29.9, 31.5, 54.8 (C-1), 122.4, 125.6, 127.8, 128.2, 136.9, 152.9, (C-4); IR (film): -1 = 3063, 2982, 2922, 1553, 1470, 1456, 1331, 1198, 1153, 1071, 1026, 914, 874, 853, 762, 729, 696; MS (APCI), m/z (%): 522 (100) [M + ], 324 (25), 134 (27); HRMS (CI), m/z: calc for C 30 H 51 NO 2 S 2, found (hex-3-yn-1-ylsulfonyl)benzo[d]thiazole (5e) Purification by flash chromatography (petroleum ether:etoac = 10:1 -> 4:1) gave sulfone 5e (228 mg, 86%). Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = 1.80 (t, J = 2.3 Hz, 3H, H-6), (m, 2H, H-2), (m, 2H, H-3), 3.25 (t, J = 8.2 Hz, 2H, H-2), 7.64 (pd, J = 7.2, 1.5 Hz, 2H), 8.03 (dd, J = 7.2, 2.1 Hz, 1H), 8.26 (dd, J = 7.4, 2.0 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 14.4, 21.2, 25.8, 60.6, 75.9, 78.2, 122.5, 125.9, 128.0, 128.5, 137.4, 152.8, (C-1); IR (film): -1 = 3062, 2983, 2921, 1555, 1468, 1335, 1197, 1152, 1026, 914, 874, 762, 729; MS (APCI), m/z (%): 280 (100) [M + ], 281 (29), 199 (31), 145 (24); HRMS (APCI), m/z: calc for C 13 H 13 NO 2 S 2, found (hex-5-en-1-ylsulfonyl)benzo[d]thiazole (5f) Purification by flash chromatography (petroleum ether:etoac = 10:1 -> 4:1) gave sulfone 5f (250 mg, 89%). Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = (m, 2H), 1.67 (dt, J = 14.6, 6.7 Hz, 2H), 2.34 (dt, J = 12.1, 7.6 Hz, 2H, H-5), 3.48 (dd, J = 9.3, 7.0 Hz, 2H, H-2), (m, 2H, H-7), 5.65 (ddt, J = 16.1, 11.2, 6.4 Hz, 1H, H-6), 7.63 (pd, J = 7.2, 1.3 Hz, 2H), 8.01 (dd, J = 7.2, 1.7 Hz, 1H), 8.22 (dd, J = 7.3, 1.5 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): δ = 23.2, 28.7, 31.5 (C-5), 55.6 (C-2), 115.8, , , , , 133.8, , , (C-1); IR (film): -1 = 3063, 2951, 2924, 2853, 1557, 1471, 1458, 1317, 1144, 1122, 853, 762; MS (APCI), m/z (%): 282 (100) [M + ], 283 (38), 195 (19), 137 (19); HRMS (APCI), m/z: calc for C 13 H 15 NO 2 S 2, found ((4-((tert-butyldiphenylsilyl)oxy)butyl)sulfonyl)benzo[d]thiazole (5g) S-7

8 Purification by flash chromatography (petroleum ether:etoac = 20:1 -> 10:1) gave sulfone 5g (449 mg, 88%). Obtained characterization data were in agreement with those published in the literature. 6 Self-condensation of sulfone 5a 2-((benzo[d]thiazol-2-ylmethyl)sulfonyl)benzo[d]thiazole (7) A solution of sulfone 5a (200 mg, 0.94 mmol, 1.0 equiv) in THF (9.4 ml, 0.10 M) was cooled to -78 C and stirred for 10 min at this temperature. A solution of LiN(TMS) 2 in THF (10.3 ml, 1.03 mmol, 1.1 equiv, 1.0M solution in THF) was added dropwise and the resulting mixture was stirred at -78 C for 2h. A 10% solution of HCl in MeOH (10 ml) was added and the resulting mixture was allowed to warm to rt. The whole mixture was extracted with EtOAc (3x20 ml) and the resulting organic layers were combined, washed with brine (15 ml), dried over MgSO 4, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on SiO 2 (petroleum ether/etoac = 10:1 -> 4:1 -> 2:1) yielding compound 7 (99 mg, 30.5% (61% after recalculation)) as yellow crystals. Mp C (lit C); 1 H NMR (CDCl 3, 300 MHz): = 5.32 (s, 2H, H-2), (m, 2H), (m, 2H), 7.86 (dd, J = 7.7, 1.0 Hz, 1H), 7.97 (dd, J = 13.0, 4.8 Hz, 2H), 8.27 (d, J = 7.8 Hz, 1H); 13 C NMR (75 MHz, CDCl3): = 59.0 (C-2), 121.9, 122.6, 124.0, 126.0, 126.3, 126.8, 128.0, 128.5, 136.5, 137.4, 152.7, 153.0, (C-3), (C-1); IR (film): max /cm -1 = 2986 (w), 2923 (w), 2911 (w), 1556 (w), 1504 (m), 1469 (s), 1434 (m), 1421 (w), 1394 (w), 1338 (s), 1317 (s), 1280 (w), 1240 (m), 1201 (m), 1155 (s), 1128 (m), 1097 (m), 1088 (m), 1064 (w), 1028 (m), 1014 (w), 910 (m), 856 (m), 762 (s), 731 (s); MS (CI), m/z (%): 347 (M +, 13), 311 (5), 283 (29), 178 (36), 164 (33), 150 (100), 136 (100), 104 (65); HRMS (CI), m/z: calc for C 15 H 11 N 2 O 2 S 3, found ; El. an. for C 15 H 10 N 2 O 2 S 3, calc. C 52.00, H 2.91, N 8.09; found C 52.06, H 3.09, N Heterosulfonyl ketones (4) and esters (11) General procedure A solution of sulfone (1.0 mmol, 1.0 equiv) in THF (5 ml, 0.20M) was cooled to -78 C and LiHMDS (1.0M sol. in THF) (2.2 ml, 2.2 mmol, 2.2 equiv) was added dropwise. A color of the reaction mixture turned from colorless or slightly yellow to orange/red. Immediately after, a solution of acylating agent (acyl halide, carboxylic acid anhydride or acyl imidazole 7 ) or alkoxy carbonylating agent (alkoxy chloroformate, alkoxy imidazoylformate 8 or Boc 2 O) (1.1 mmol, 1.1 equiv) in THF (0.5 ml) 9 was added. The color of the reaction mixture faded within few minutes. The resulting mixture was stirred at -78 C for 30 min, allowed to warm to 0 C within 1h and stirred at 0 C for a further 30 min before sat. aq. sol. of NH 4 Cl (15 ml) was added. The whole mixture was extracted with EtOAc (3x75 ml) and the combined organic layers were washed with brine (50 ml), dried over MgSO 4, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on SiO 2. S-8

9 2-(benzo[d]thiazol-2-ylsulfonyl)-1-phenylethanone (4a) Starting from sulfone 5a (100 mg, 0.47 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 4:1->2:1->1:1): - Using BzCl as acylating agent (Table 1, entry 4), the reaction yielded 143 mg (96%) of 4a. - Using Bz 2 O as acylating agent (Table 1, entry 16), the reaction yielded 137 mg (92%) of 4a. - Using Bz-Im as acylating agent (Table 1, entry 17), the reaction yielded 137 mg (92%) of 4a. - Using Bz-CN as acylating agent (Table 1, entry 18), the reaction yielded 135 mg (92%) of 4a. The reaction performed with 2.0 g (9.4 mmol) of sulfone 5a and 1.31 ml (11.4 mmol) of BzCl 10 gave 2.89 g (97%) of 4a. TLC (petroleum ether:etoac = 2:1) Mp = C, lit C; 1 H-NMR (300 MHz, CDCl 3 ): = 5.22 (s, 2H, H-2), (m, 2H), (m, 3H), 7.94 (dd, J = 8.4, 1.2 Hz, 2H), 8.01 (dd, J = 7.0, 2.2 Hz, 1H), 8.20 (dd, J = 7.2, 2.1 Hz, 1H); 13 C- NMR (75 MHz, CDCl 3 ): = 61.4 (C-2), 122.6, 125.7, 127.9, 128.4, , , 134.9, 135.6, 137.3, 152.6, (C-1), (C-3); IR (film): -1 = 3063 (w), 2959 (w), 2925 (w), 2921 (w), 2919 (w), 1683 (s), 1598 (m), 1471 (m), 1338 (s), 1155 (s), 991 (m), 760 (s), 731 (s), 688 (s); MS (APCI), m/z (%): 318 (100) [M + +1], 319 (20), 236 (9), 105 (11); El. an. for C 15 H 11 NO 3 S 2, calc. C 56.76, H 3.49, N 4.41; found C 56.78, H 3.11, N (benzo[d]thiazol-2-ylsulfonyl)propan-2-one (4b) Starting from sulfone 5a (100 mg, 0.47 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 4:1->2:1->1:1): - Using AcCl as acylating agent (Table 5, entry 1), the reaction yielded 108 mg (90%) of 4b. - Using Ac 2 O as acylating agent (Table 5, entry 2), the reaction yielded 110 mg (92%) of 4b. - Using Ac-Im as acylating agent (Table 5, entry 3), the reaction yielded 107 mg (89%) of 4b. The reaction performed with 2.0 g (9.4 mmol) of sulfone 5a and 0.8 ml (11.4 mmol) of AcCl 12 gave 2.15 g (90%) of 4b. S-9

10 TLC (petroleum ether:etoac = 2:1) Mp = C, lit C; 1 H-NMR (300 MHz, CDCl 3 ): = 2.46 (s, 3H, H-4), 4.60 (s, 2H, H-2), (m, 2H), 8.03 (dd, J = 8.0, 1.4 Hz, 1H), 8.22 (dd, J = 6.7, 1.5 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 31.7 (C-4), 65.6 (C-2), 122.6, 125.8, 128.0, 128.5, 137.1, 152.6, (C-1), (C-3); IR (film): -1 = 2990 (w), 2952 (w), 2925 (w), 2853 (w), 1726 (s), 1556 (w), 1471 (m), 1334 (s), 1159 (s), 1028 (m), 854 (m), 762 (s); MS (APCI), m/z (%): 256 (100) [M + +1], 258 (15), 214 (27), 136 (13); El. an. for C 10 H 9 NO 3 S 2, calc. C 46.82, H 3.35, N 5.49; found C 46.82, H 3.35, N (benzo[d]thiazol-2-ylsulfonyl)-1-cyclohexyloctan-1-one (4c) Starting from sulfone 5b (100 mg, 0.34 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 10:1): - Using AcCl as acylating agent (Table 5, entry 4), the reaction yielded 114 mg (83%) of 4c. - Using Ac-Im as acylating agent (Table 5, entry 5), the reaction yielded 126 mg (92%) of 4c. TLC (petroleum ether:etoac = 4:1) Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = 0.82 (t, J = 6.7 Hz, 3H, H-13), (m, 13H), (m, 6H), (m, 1H), 2.78 (tt, J = 11.3, 3.3 Hz, 1H, H-4), 4.73 (dd, J = 10.7, 3.5 Hz, 1H, H-2), 7.64 (pd, J = 7.2, 1.6 Hz, 1H), 7.65 (p, J = 7.2 Hz, 1H), 8.01 (dd, J = 7.2, 1.8 Hz, 1H), 8.25 (dd, J = 7.4, 1.9 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 14.1 (C-13), 22.6, 25.2, 25.8, 26.0, 27.1, 27.3, 27.6, 28.5, 29.0, 31.4, 52.8 (C-4), 72.7 (C-2), 122.5, 125.9, 127.9, 128.4, 137.4, 152.8, (C-1), (C-3); IR (film): -1 = 2991 (w), 2952 (w), 2927 (w), 2852 (w), 1728 (s), 1554 (w), 1475 (m), 1161 (s), 1029 (m), 853 (m), 761 (s); MS (APCI), m/z (%): 408 (100) [M + ], 409 (21), 105 (40); El. an. for C 21 H 29 NO 3 S 2, calc. C 61.88, H 7.17, N 3.44; found C 62.03, H 7.29, N S-10

11 2-(benzo[d]thiazol-2-ylsulfonyl)-1-mesityloctan-1-one (4d) Starting from sulfone 5b (100 mg, 0.34 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 10:1) yielding 112 mg (89%) of 4d (Table 5, entry 6). TLC (petroleum ether:etoac = 4:1) Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = 0.86 (t, J = 6.7 Hz, 3H, H-13), (m, 4H), 1.36 (dt, J = 14.6, 7.3 Hz, 2H, H-10), 1.51 (tt, J = 12.1, 6.2 Hz, 2H, H-9), 1.98 (s, 3H, H-15), 2.29 (s, 6H, H-14, partial overlap), (m, 2H, H-8), 5.38 (t, J = 6.5 Hz, 1H, H-2), 6.55 (s, 2H, H-6), (m, 2H), 7.92 (d, J = 7.7 Hz, 1H), 8.12 (dd, J = 7.6, 0.8 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = (C-13), 20.6 (C-14), 21.0 (C-15), 22.6, 24.9, 27.6, 29.3, 31.4, 74.2 (C-2), 122.2, 125.3, 127.6, 128.0, 129.4, 135.5, 136.0, 137.2, 140.6, 152.4, (C-1), (C-3); IR (film): -1 = 3063 (w), 3059 (w), 2958 (w), 2925 (w), 2920 (w), 2920 (w), 1681 (s), 1597 (m), 1471 (m), 1331 (s), 1156 (s), 990 (m), 761 (s), 730 (s), 689 (s); MS (APCI), m/z (%): 444 (100) [M + ], 445 (26), 324 (51); El. an. for C 24 H 29 NO 3 S 2, calc. C 64.98, H 6.59, N 3.16; found C 65.21, H 6.23, N (benzo[d]thiazol-2-ylsulfonyl)-1-phenoxynonan-2-one (4e) Starting from sulfone 5b (100 mg, 0.34 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 10:1->4:1) yielding 125 mg (86%) of 4e as yellowish oil (Table 5, entry 7). TLC (petroleum ether:etoac = 4:1) 1 H-NMR (300 MHz, CDCl 3 ): = 0.83 (t, J = 6.8 Hz, 3H, H-10), (m, 8H), (m, 2H, H-5), 4.89 (dd, J = 17.1 Hz, 2H, H-4), 5.02 (dd, J = 10.4, 4.0 Hz, 1H, H-2), 6.90 (d, J = 8.0 Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H), (m, 2H), (m, 2H), 7.99 (dd, J = 7.1, 2.2 Hz, 1H), 8.21 (dd, J = 7.2, 2.1 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 14.1 (C-10), 22.5, 26.7, 26.9, 28.8, 31.4, 70.1 (C-4), 73.6 (C-2), 114.8, S-11

12 122.25, , 125.9, 128.0, 128.5, 129.8, 137.3, 152.7, 157.4, (C-1), (C-3); IR (film): -1 = 3062 (w), 2928 (s), 1739 (s), 1589 (m), 1494 (m), 1467 (m), 1334 (s), 1149 (s), 758 (m); MS (APCI), m/z (%): 432 (100) [M + ], 433 (24), 368 (15), 298 (74), 233 (11); El. an. for C 22 H 25 NO 4 S 2, calc. C 61.23, H 5.84, N 3.25; found C 60.83, H 5.78, N ethyl 3-(benzo[d]thiazol-2-ylsulfonyl)-2-oxononanoate (4f) Starting from sulfone 5b (100 mg, 0.34 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 4:1->2:1) yielding 104 mg (78%) of 4f as yellow oil (Table 5, entry 8). TLC (petroleum ether:etoac = 2:1) Keto/enol forms of 11f = ~1:1. Peaks belonging to enol form are marked with*. 1 H-NMR (300 MHz, CDCl 3 ): = 0.84 (t, J = 6.7 Hz, 3H, H-10) (m, 8H), (m, 2H), 4.12 (q, J = 7.2 Hz, 2H, H-11*), 4.30 (q, J = 7.2 Hz, 2H, H-11), 5.55 (t, J = 7.2 Hz, 1H, H-2), (m, 2H), (m, 1H), (m, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 14.1 (C-10*), 14.4 (C-10), 21.23, 22.56, 26.18, 26.87, 28.06, 28.91, 31.24, 31.37, 60.6 (C-11), 63.8 (C-11*), 68.6 (C-2*), 122.6, 125.7, 128.0, 127.8, 128.6, 137.2, 152.3, 160.3, 164.3, (C-4), (C-3); IR (film): -1 = 3320 (w), 2955 (m), 2928 (s), 2856 (m), 1731 (s), 1705 (s), 1674 (s), 1470 (s), 1330 (m), 1150 (s), 1020 (m), 852 (m), 762 (m), 729 (s); MS (APCI), m/z (%): 398 (100) [M + ], 399 (22), 370 (48), 334 (31), 298 (30), 281 (58), 199 (14), 136 (11); El. an. for C 18 H 23 NO 5 S 2, calc. C 54.39, H 5.83, N 3.52; found C 54.42, H 5.89, N (benzo[d]thiazol-2-ylsulfonyl)-1-chloroundecan-4-one (4g) Starting from sulfone 5b (100 mg, 0.34 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 10:1->4:1) yielding 110 mg (81%) of 4g as yellow oil (Table 5, entry 9). S-12

13 TLC (petroleum ether:etoac = 4:1) 1 H-NMR (300 MHz, CDCl 3 ): = 0.83 (t, J = 6.7 Hz, 3H, H-12), (m, 8H), (m, 4H, H-5 and H-7), 2.89 (dt, J = 19.1, 6.8 Hz, 1H, one of H-4), 3.13 (dt, J = 19.1, 6.8 Hz, 1H, one of H-4), 3.58 (pd, J = 6.5, 2.6 Hz, 2H, H-6), 4.55 (dd, J = 10.7, 3.9 Hz, 1H, H-2), 7.63 (pd, J = 7.2, 1.4 Hz, 2H), 8.02 (dd, J = 7.1, 1.9 Hz, 1H), 8.24 (dd, J = 7.3, 1.9 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = (C-12), 22.6, 26.2, 26.8, 27.0, 28.9, 31.4, 41.6, 44.0, 74.6 (C-2), 122.5, 125.9, 128.0, 128.5, 137.3, 152.7, (C-1), (C-3); IR (film): -1 = 2955 (m), 2928 (s), 2856 (m), 1720 (s), 1467 (s), 1330 (s), 1315 (s), 1144 (m), 1022 (m), 852 (m), 762 (m), 729 (s); MS (APCI), m/z (%): 402 (11) [M + ], 404 (7), 366 (100), 302 (40); El. an. for C 18 H 24 ClNO 3 S 2, calc. C 53.78, H 6.02, N 3.48; found C 53.92, H 5.91, N (benzo[d]thiazol-2-ylsulfonyl)-1-cyclohexylethanoe (4h) Starting from sulfone 5a (200 mg, 0.94 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 4:1->2:1) yielding sulfone 4h (252 mg, 83%) as slightly yellow crystals (Table 4, entry 3). TLC (petroleum ether:etoac = 2:1) Keto/enol forms of 4h = ~9:1. Peaks belonging to enol form are marked with*. Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = (m, 6H), (m, 4H), (ddd, J = 14.0, 7.5, 3.4 Hz, 1H, H-4), 4.68 (s, 2H, H-2), 5.30 (s, 1H, H-2*), (m, 2H), 8.01 (dd, J = 7.8, 1.5 Hz, 1H), 8.19 (dd, J = 7.5, 1.3 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 25.4, 25.7, 27.9, 51.8 (C-4), 62.7 (C-2), 122.6, 125.6, 127.9, 128.3, 137.1, 152.5, (C-1), (C-3); IR (film): -1 = 2940 (m), 2932 (m), 2925 (m), 2909 (w), 2894 (w), 2857 (m), 1716 (m), 1706 (s), 1473 (s), 1450 (m), 1336 (s), 1317 (s), 1294 (m), 1278 (m), 1157 (s), 1147 (s), 1128 (s), 1088 (m), 1062 (m), 1028 (m), 999 (s), 902 (m), 856 (s), 760 (s), 731 (s), 708 (s), 692 (s); MS (APCI), m/z (%): 324 (100) [M + ], 198 (60), 134 (29); El. an. for C 15 H 17 NO 3 S 2, calc. C 55.70, H 5.30, N 4.33; found C 55.79, H 5.18, N S-13

14 methyl 2-(benzo[d]thiazol-2-ylsulfonyl)acetate (11a) Starting from sulfone 5a (100 mg, 0.34 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 4:1->2:1->1:1): - Using ClCOOMe as alkoxycarbonylating agent (Table 6, entry 1), the reaction yielded 120 mg (94%) of 11a. - Using Im-COOMe as alkoxycarbonylating agent (Table 6, entry 2), the reaction yielded 113 mg (89%) of 11a. - Using NC-COOMe as alkoxycarbonylating agent (Table 6, entry 3), the reaction yielded 116 mg (91%) of 11a. The reaction performed with 3.0 g (14.1 mmol) of sulfone 5a and 1.3 ml (16.9 mmol) of ClCOOMe 14 gave 3.74 g (98%) of 11a. TLC (petroleum ether:etoac = 2:1) Keto/enol forms of 11a = ~7:1. Peaks belonging to enol form are marked with*. Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = 3.66 (s, 3H, H-4), 3.73 (s, 3H, H-4*), 4.59 (s, 2H, H-2), 5.31 (s, 1H, H-2*), (m, 2H), 8.02 (dd, J = 7.1, 2.1 Hz, 1H), 8.21 (dd, J = 7.3, 2.2 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 52.4 (C-4*), 53.5 (C-4), 58.7 (C-2), 122.6, 125.7, 127.9, 128.4, 137.1, 152.6, (C-1), (C-3); IR (film): -1 = 2992 (w), 2984 (w), 2938 (w), 1803 (m), 1741 (s), 1471 (s), 1342 (s), 1155 (s), 1122 (s), 762 (s), 729 (s); MS (APCI), m/z (%): 272 (100) [M + ], 240 (35), 214 (7); El. an. for C 10 H 9 NO 4 S 2, calc. C 44.27, H 3.34, N 5.16; found C 44.67, H 3.12, N allyl 2-(benzo[d]thiazol-2-ylsulfonyl)acetate (11b) Starting from sulfone 5a (100 mg, 0.47 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 4:1->1:1) yielding 132 mg (95%) of 11b (Table 6, entry 34). The reaction performed with 1.0 g (4.69 mmol) of sulfone 13a and ml (5.63 mmol) of ClCOOCH 2 CH=CH 2 15 gave 1.31 g (94%) of 11b. S-14

15 TLC (petroleum ether:etoac = 2:1) Keto/enol forms of 11b = ~7:1. Peaks belonging to enol form are marked with*. Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = 4.60 (td, J = 2.7, 1.3 Hz, 2H, H-4), 4.61 (s, 2H, H-2), (m, 1H, H-2*), 5.18 (ddd, J = 10.5, 2.2, 1.1 Hz, 1H, H-6), 5.24 (ddd, J = 17.3, 2.8, 1.4 Hz, 1H, H-6), (m, 2H, H-6*), 5.77 (ddt, J = 22.2, 10.4, 5.9 Hz, 1H, H-5), (m, 1H, H-5*), (m, 2H), 8.02 (dd, J = 7.0, 1.9 Hz, 1H), 8.22 (dd, J = 7.4, 2.1 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 58.8 (C-4), 67.3 (C-2), 119.8, 122.6, 125.7, 128.0, 128.5, 130.6, 137.2, 152.6, (C-1), (C-3); IR (film): -1 = 3089 (w), 3073 (w), 2992 (w), 2984 (w), 2938 (w), 1803 (m), 1741 (s), 1650 (w), 1554 (w), 1519 (m), 1471 (s), 1423 (m), 1342 (s), 1317 (s), 1300 (s), 1276 (s), 1240 (s), 1195 (s), 1155 (s), 1122 (s), 1088 (s), 1028 (s), 987 (s), 935 (s), 854 (s), 796 (s), 762 (s), 729 (s), 710 (s), 694 (s), 652 (m), 644 (s), 633 (s), 625 (s), 617 (s), 609 (m); MS (APCI), m/z (%): 298 (100) [M + ], 240 (24); El. an. for C 12 H 11 NO 4 S 2, calc. C 48.47, H 3.73, N 4.71; found C 48.82, H 3.65, N tert-butyl 2-(benzo[d]thiazol-2-ylsulfonyl)acetate (11c) Starting from sulfone 5a (100 mg, 0.47 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 4:1): - Using Boc 2 O as alkoxycarbonylating agent (Table 6, entry 5), the reaction yielded 138 mg (94%) of 11c. - Using Im-COOtBu as alkoxycarbonylating agent (Table 6, entry 6), the reaction yielded 144 mg (89%) of 11c. The reaction performed with 2.0 g (9.38 mmol) of sulfone 5a and 2.46 g (11.3 mmol) of Boc 2 O 16 gave 2.88 g (98%) of 11c. TLC (petroleum ether:etoac = 4:1) Keto/enol forms of 11c = ~6:1. Peaks belonging to enol form are marked with*. Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = 1.34 (s, 9H, H-5), 1.48 (s, 9H, H5*), 4.49 (s, 2H, H-2), 7.63 (p, J = 7.2, 1.5 Hz, 2H), 8.03 (dd, J = 7.1, 1.8 Hz, 1H), 8.23 (dd, J = 7.2, 1.7 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 27.8 (C-5), 28.2 (C-5*), 60.1 (C-2), 84.6 (C-4), 122.6, 125.7, 127.9, 128.4, 137.0, 152.7, (C-1), S-15

16 (C-3); IR (film): -1 = 2977 (w), 2935 (w), 1794 (m), 1732 (s), 1471 (m), 1339 (s), 1144 (s), 1088 (s), 761 (s), 629 (s); MS (ESI), m/z (%): 336 (33) [M+Na + ], 258 (100), 240 (19); El. an. for C 13 H 15 NO 4 S 2, calc. C 49.82, H 4.82, N 4.47; found C 50.13, H 4.98, N methyl 2-(benzo[d]thiazol-2-ylsulfonyl)-2-phenylacetate (11d) Starting from sulfone 5c (100 mg, 0.35 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 4:1->1:1): - Using ClCOOMe as alkoxycarbonylating agent (Table 6, entry 7), the reaction yielded 106 mg (88%) of 11d. - Using Im-COOMe as alkoxycarbonylating agent (Table 6, entry 8), the reaction yielded 113 mg (94%) of 11d. - Using NC-COOMe as alkoxycarbonylating agent (Table 6, entry 9), the reaction yielded 110 mg (92%) of 11d. TLC (petroleum ether:etoac = 2:1) Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = 3.78 (s, 3H, H-4), 5.77 (s, 1H, H-2), (m, 3H), (m, 2H), (m, 1H), (m, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 53.7 (C-4), 73.6 (C-2), 122.5, 125.7, 126.4, 127.9, 128.4, 129.2, 130.3, 130.9, 137.4, 152.5, 164.5, 164.7; IR (film): -1 = 3072 (s), 3063 (m), 2993 (w), 2937 (w), 1740 (s), 1472 (s), 1341 (s), 1144 (s), 1121 (s), 762 (s), 729 (s); MS (APCI), m/z (%): 348 (100) [M + ], 284 (26), 224 (12), 149 (7); El. an. for C 16 H 13 NO 4 S 2, calc. C 55.32, H 3.77, N 4.03; found C 55.67, H 3.60, N tert-butyl 2-(benzo[d]thiazol-2-ylsulfonyl)-2-phenylacetate (11e) Starting from sulfone 5c (100 mg, 0.35 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 4:1->2:1): - Using Boc 2 O as alkoxycarbonylating agent (Table 6, entry 10), the reaction yielded 124 mg (91%) of Using Im-COOtBu as alkoxycarbonylating agent (Table 6, entry 11), the reaction yielded 134 mg (98%) of 11e. S-16

17 TLC (petroleum ether:etoac = 4:1) Keto/enol forms of 11e = ~5:1. Peaks belonging to enol form are marked with*. Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = 1.38 (s, 9H, H-5), 1.49 (s, J = 5.5 Hz, 9H, H-5*), 5.71 (s, 1H, H-2), (m, 3H), (m, 4H), 7.96 (d, J = 7.7 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 27.7 (C-5), (C-5*), 74.2 (C-2), 84.6 (C-4), 122.3, 125.5, 126.6, 127.7, 128.1, 128.9, 130.0, 130.8, 137.1, 152.4, (C-2), (C-3); 53.7 (C-4), 73.6 (C-2), 122.5, 125.7, 126.4, 127.9, 128.4, 129.2, 130.3, 130.9, 137.4, 152.5, (C-3); IR (film): -1 = 3071 (s), 3062 (m), 2995 (w), 2938 (w), 1805 (w), 1742 (s), 1471 (s), 1332 (s), 1143 (s), 1112 (s), 761 (s), 728 (s); MS (APCI), m/z (%): 390 (100) [M + ], 200 (31); El. an. for C 19 H 19 NO 4 S 2, calc. C 58.59, H 4.92, N 3.60; found C 58.21, H 5.02, N methyl 2-(benzo[d]thiazol-2-ylsulfonyl)-2-lignocerate (11f) Starting from sulfone 5d (100 mg, 0.19 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 20:1->10:1): - Using ClCOOMe as alkoxycarbonylating agent (Table 6, entry 12), the reaction yielded 98 mg (88%) of 11f. - Using Im-COOMe as alkoxycarbonylating agent (Table 6, entry 13), the reaction yielded 104 mg (94%) of 11f. - Using NC-COOMe as alkoxycarbonylating agent (Table 6, entry 14), the reaction yielded 103 mg (93%) of 11f. TLC (petroleum ether:etoac = 10:1) Keto/enol forms of 11f = ~8:1. Peaks belonging to enol form are marked with*. Mp = C; 1 H-NMR (300 MHz, CDCl 3 ): = 0.88 (t, J = 6.7 Hz, 3H, H-6), (m, 40H), (m, 2H, H-5), 3.64 (t, J = 6.7 Hz, 2H, H-5*), 3.74 (s, 3H, H-4), 4.44 (dd, J = 8.8, 6.0 Hz, 1H, H-2), 5.30 (s, 1H*), (m, 2H), 8.03 (dd, J = 7.1, 1.9 Hz, 1H), 8.26 (dd, J = 7.2, 1.8 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 14.3 (C-6), 22.9, 26.4, 27.1, 29.2, 29.3, 29.6, 29.8, 29.9, 32.1, 53.5 (C-4), 70.0 (C-2), 122.5, 125.9, 127.9, 128.4, 137.4, 152.8, (C-1), (C-3); IR (film): -1 = 3061 (w), 2996 (s), 2929 (s), S-17

18 1801 (w), 1744 (s), 1472 (m), 1331 (s), 1143 (s), 1122 (s), 761 (s), 727 (s); MS (APCI), m/z (%): 580 (100) [M + ], 581 (37); El. an. for C 32 H 53 NO 4 S 2, calc. C 66.28, H 9.21, N 2.42; found C 66.49, H 9.17, N methyl 2-(benzo[d]thiazol-2-ylsulfonyl)hept-5-ynoate (11g) Starting from sulfone 5e (100 mg, 0.19 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 10:1->4:1->2:1->1:1): - Using ClCOOMe as alkoxycarbonylating agent (Table 6, entry 15), the reaction yielded 112 mg (88%) of 11g as yellowish oil. - Using Im-COOMe as alkoxycarbonylating agent (Table 6, entry 16), the reaction yielded 118 mg (93%) of 11g as yellowish oil. - Using NC-COOMe as alkoxycarbonylating agent (Table 6, entry 17), the reaction yielded 119 mg (94%) of 11g as yellowish oil. TLC (petroleum ether:etoac = 2:1) Keto/enol forms of 11g = ~8:1. Peaks belonging to enol form are marked with*. 1 H-NMR (300 MHz, CDCl 3 ): = 1.73 (t, J = 2.3 Hz, 3H, H-9), (m, 1H), (m, 3H), (m, 2H, H-6*), 3.74 (s, 3H, H-4), 4.70 (dd, J = 7.8, 6.1 Hz, 1H, H-2), 5.31 (s, 1H*), (m, 1H), (m, 1H*), 7.63 (p, J = 7.2 Hz, 1H), 7.65 (p, J = 7.2 Hz, 1H), (m, 2H*), 8.03 (dd, J = 7.2, 2.1 Hz, 1H), 8.26 (dd, J = 7.4, 2.0 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 3.6, 14.4, 16.7, 21.2, 25.8, 53.6, 60.6, 68.9, 75.8, 78.6, 122.5, 125.9, 128.0, 128.5, 137.4, 152.8, (C-1), (C-3); IR (film): -1 = 2954 (w), 2917 (w), 1739 (s), 1471 (m), 1436 (m), 1336 (s), 1149 (s), 1024 (m), 854 (m), 764 (s), 731 (s), 694 (m), 640 (m); MS (APCI), m/z (%): 338 (100) [M + ], 339 (12), 306 (16); El. an. for C 15 H 15 NO 4 S 2, calc. C 53.40, H 4.48, N 4.15; found C 53.71, H 4.63, N allyl 2-(benzo[d]thiazol-2-ylsulfonyl)hept-5-ynoate (11h) Starting from sulfone 5e (100 mg, 0.36 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 10:1->4:1); the reaction yielded 116 mg (89%) of 11h as yellow oil (Table 6, entry 18). S-18

19 TLC (petroleum ether:etoac = 4:1) Keto/enol forms of 11h = ~7:1. Peaks belonging to enol form are marked with*. 1 H-NMR (300 MHz, CDCl 3 ): = 1.75 (t, J = 2.3 Hz, 3H, H-11), (m, 4H), (m, 2H*), 4.61 (dd, J = 5.8, 1.2 Hz, 2H, H-4), 4.72 (dd, J = 7.6, 6.3 Hz, 1H, H-2), 5.14 (dd, J = 10.4, 1.1 Hz, 1H, H-6), 5.22 (dd, J = 17.2, 1.3 Hz, 1H, H-6), (m, 2H, H-6*), 5.73 (ddt, J = 16.2, 10.5, 5.8 Hz, 1H, H-5), 7.37 (t, J = 8.1 Hz, 1H*), 7.47 (t, J = 7.7 Hz, 1H*), 7.63 (p, J = 7.2 Hz, 1H), 7.65 (p, J = 7.2 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H*), 7.98 (d, J = 8.3 Hz, 1H*), 8.02 (dd, J = 7.0, 1.8 Hz, 1H), 8.26 (dd, J = 7.2, 1.8 Hz, 1H); 13 C- NMR (75 MHz, CDCl 3 ): = 3.7, 16.7, 25.8, 67.3, 68.9, 75.9, 78.6, 119.6, 122.5, 126.0, 127.9, 128.5, 130.8, 137.4, 152.9, 164.2, 164.5; IR (film): -1 = 3071 (w), 3063 (w), 2934 (w), 2919 (w), 2855 (w), 1739 (s), 1677 (w), 1650 (w), 1554 (w), 1471 (s), 1149 (s), 1024 (s), 941 (s), 854 (s), 764 (s), 731 (s); MS (APCI), m/z (%): 364 (100) [M + ], 365 (17), 306 (7); El. an. for C 17 H 17 NO 4 S 2, calc. C 56.18, H 4.71, N 3.85; found C 55.82, H 4.83, N methyl 2-(benzo[d]thiazol-2-ylsulfonyl)hept-6-enoate (11i) Starting from sulfone 5f (100 mg, 0.36 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 10:1->4:1): - Using ClCOOMe as alkoxycarbonylating agent (Table 6, entry 19), the reaction yielded 105 mg (87%) of 11i (yellow oil). - Using Im-COOMe as alkoxycarbonylating agent (Table 6, entry 20), the reaction yielded 115 mg (95%) of 11i (yellow oil). - Using NC-COOMe as alkoxycarbonylating agent (Table 6, entry 21), the reaction yielded 113 mg (94%) of 11i (yellow oil). TLC (petroleum ether:etoac = 2:1) Keto/enol forms of 11i = ~11:1. Peaks belonging to enol form are marked with*. 1 H-NMR (300 MHz, CDCl 3 ): = (m, 2H), 2.11 (dt, J = 14.2, 4.7 Hz, 2H), (m, 2H), 3.73 (s, 3H, H-4), 4.47 (td, J = 7.9, 5.4 Hz, 1H, H-2), 4.95 (dd, J = 10.5, 1.3 Hz, 1H, H-9), 5.05 (dt, J = 3.0, 1.5 Hz, 1H, H-9), 5.73 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H, H-8), 7.64 (pd, J = 7.2, 1.5 Hz, 2H), 8.03 (dd, J = 7.2, 2.1 Hz, S-19

20 1H), 8.25 (dd, J = 7.4, 1.9 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 25.8, 26.3, 33.1, 53.5 (C-4), 69.8 (C-2), 115.9, 122.5, 125.9, 127.9, 128.5, 137.2, 137.3, 152.8, (C-1), (C-3); IR (film): -1 = 2940 (w), 2932 (w), 2923 (w), 2911 (w), 2903 (w), 1739 (s), 1641 (w), 1554 (w), 1471 (m), 1338 (s), 1149 (s), 1024 (m), 854 (m), 764 (s), 731 (s), 619 (m); MS (APCI), m/z (%): 340 (100) [M + ], 341 (21), 308 (7); El. an. for C 15 H 17 NO 4 S 2, calc. C 53.08, H 5.05, N 4.13; found C 52.95, H 5.17, N methyl 2-(benzo[d]thiazol-2-ylsulfonyl)-5-((tert-butyldiphenylsilyl)oxy)pentanoate (11j) Starting from sulfone 5g (100 mg, 0.20 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 10:1->4:1): - Using ClCOOMe as alkoxycarbonylating agent (Table 6, entry 22), the reaction yielded 99 mg (89%) of 11j (yellow oil). - Using Im-COOMe as alkoxycarbonylating agent (Table 6, entry 23), the reaction yielded 104 mg (93%) of 11j (yellow oil). - Using Im-COOMe as alkoxycarbonylating agent (Table 6, entry 24), the reaction yielded 102 mg (91%) of 11j (yellow oil). Keto/enol forms of 11j = ~6:1. Peaks belonging to enol form are marked with*. 1 H-NMR (300 MHz, CDCl 3 ): = 0.99 (s, 9H, H-9), (m, 2H), (m, 2H), 3.68 (t, J = 5.9 Hz, 2H, H-7), 3.73 (s, 3H, H-4), 4.62 (dd, J = 9.6, 5.4 Hz, 1H, H-2), 5.30 (s, 1H*), (m, 6H), (m, 6H), (m, 2H*), 8.02 (dd, J = 6.7, 2.1 Hz, 1H), 8.24 (dd, J = 7.2, 2.3 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 19.3, 23.6, 26.9, 29.7, 53.5 (C-4), 63.0, 69.7, 122.5, 126.0, 127.9, 128.4, 129.9, 133.6, 135.7, 137.4, 152.9, (C-1), (C-3); IR (film): -1 = 2957 (w), 2938 (w), 2929 (w), 2855 (w), 1747 (s), 1471 (m), 1429 (m), 1340 (s), 1317 (m), 1151 (s), 1111 (s), 910 (s), 764 (s), 704 (s), 600 (w); MS (APCI), m/z (%): 568 (100) [M + ], 569 (36), 490 (96), 432 (36), 312 (47); El. an. for C 29 H 33 NO 5 S 2 Si, calc. C 61.34, H 5.86, N 2.78; found C 60.94, H 5.91, N allyl 2-(benzo[d]thiazol-2-ylsulfonyl)octanoate (11k) Starting from sulfone 5b (100 mg, 0.34 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 10:1->4:1); the reaction yielded 118 mg (92%) of 11k as yellow oil (Table 6, entry 25). Keto/enol forms of 11k = >20:1. Peaks belonging to enol form are marked with*. 1 H-NMR (300 MHz, CDCl 3 ): = 0.86 (t, J = 6.8 Hz, 1H, H-8), (m, 8H), (m, 2H, H-7), 4.46 (dd, J = 9.0, 5.8 Hz, 1H, H-2), 4.59 (d, J = 5.7 Hz, 2H, H-4), 5.12 (dd, J = 10.4, 1.1 Hz, 1H, H-6), 5.20 (dd, J = 17.2, 1.4 Hz, 1H, H-6), S-20

21 5.71 (ddt, J = 16.3, 10.4, 5.9 Hz, 1H, H-5), 7.63 (pd, J = 7.2, 1.5 Hz, 2H), 8.01 (dd, J = 7.0, 1.9 Hz, 1H), 8.24 (dd, J = 7.2, 1.8 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 14.1, 22.6, 26.2, 27.0, 28.8, 31.4, 67.1, 69.9, 119.6, 122.4, 125.8, 127.9, 128.4, 130.8, 137.4, 152.8, (C-1), (C-3); IR (film): -1 = 2930 (w), 2923 (w), 2861 (w), 1741 (s), 1471 (m), 1340 (s), 1319 (m), 1149 (s), 1126 (m), 854 (m), 764 (s), 731 (m), 694 (w), 636 (m); MS (APCI), m/z (%): 382 (100) [M + ], 383 (19), 324 (29), 149 (5); El. an. for C 18 H 23 NO 4 S 2, calc. C 56.67, H 6.08, N 3.67; found C 56.92, H 5.79, N S-ethyl 2-(benzo[d]thiazol-2-ylsulfonyl)ethanethioate (11l) Starting from sulfone 5a (200 mg, 0.94 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 10:1->4:1); the reaction yielded 266 mg (94%) of 11l as yellow oil (Table 7, entry 2). Keto/enol forms of 11l = 8:1. Peaks belonging to enol form are marked with*. 1 H-NMR (300 MHz, CDCl 3 ): = 1.20 (t, J = 7.5 Hz, 3H, H-5), 2.89 (q, J = 7.4 Hz, 2H, H-4), 4.11 (q, J = 7.1 Hz, 2H, H-4*), 4.71 (s, 2H, H-2), 7.62 (pd, J = 7.2, 3.6 Hz, 2H), (m, 1H), (m, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 14.3 (C-5), 15.7 (C-5*), 21.2 (C-4*), 24.9 (C-4), 60.5 (C-2*), 65.2 (C-2), 122.6, 125.7, 127.9, 128.5, 137.2, 152.6, (C-1), (C-3); IR (film): -1 = 2978 (w), 2930 (w), 1675 (s), 1471 (s), 1340 (s), 1317 (s), 1240 (m), 1159 (s), 1140 (s), 1005 (s), 974 (m), 764 (s), 731 (s), 692 (m); MS (ES), m/z (%): 302 (M + +H, 100), 253 (11), 240 (100), 216 (9), 175 (41), 170 (12), 134 (18); HRMS (ES), m/z: calc for C 11 H 12 NO 3 S 3, found ;El. an. for C 11 H 11 NO 3 S 3, calc. C 43.83, H 3.68, N 4.65; found C 43.92, H 3.86, N (benzo[d]thiazol-2-ylsulfonyl)-N,N-diethylacetamide (11m) Starting from sulfone 5a (200 mg, 0.94 mmol), the crude material was purified by flash chromatography (petroleum ether:etoac = 2:1->1:1); the reaction yielded 185 mg (63%) of 11m as white solid (Table 7, entry 3). Keto/enol forms of 11l = 8:1. Peaks belonging to enol form are marked with*. Mp C; 1 H-NMR (300 MHz, CDCl 3 ): = 1.07 (t, J = 7.1 Hz, 3H, H-5), 1.25 (t, J = 7.2 Hz, 3H, H-5), 3.34 (q, J = 7.1 Hz, 2H, H-4), 3.45 (q, J = 7.2 Hz, 2H, H-4), 4.64 (s, 2H, H-2), 7.59 (pd, J = 7.2, 1.5 Hz, 2H), 7.99 (dd, J = 7.1, 1.9 Hz, 1H), 8.21 (dd, J = 7.4, 1.9 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 12.9 and 14.6 (C-5), 41.1 and 43.3 (C-4), 58.0 (C-2), 122.6, 125.6, 127.7, 128.1, 137.4, 152.6, (C-1), (C-3); IR (film): -1 = 2969 (w), 2919 (w), 2901 (w), 1647 (s), 1461 (s), 1330 (s), 1153 (s), 1126 (s), 1086 (m), 1028 (m), 893 (m), 762 (s), 733 (s); MS (ES), m/z (%): 335 (M + +Na, 100), 313 (M + +H, 61), 240 (65), 175 (12), 170 S-21

22 (7); HRMS (ES), m/z: calc for C 13 H 16 N 2 O 3 S 2 Na, found ;El. an. for C 13 H 16 N 2 O 3 S 2, calc. C 49.98, H 5.16, N 8.97; found C 50.03, H 5.15, N Synthesis of 2-(((phenylsulfonyl)methyl)sulfonyl)benzo[d]thiazole (12b) 17 ((Iodomethyl)sulfonyl)benzene (S-6) A solution of sodium benzenesulfinate (10.0 g, mmol, 1.0 equiv) in DMF (250 ml, 0.25M) was stirred at RT for 15 min. Diiodidemethane (6.0 ml, mmol, 1.2 equiv) was added dropwise and the solution was stirred for a further 17h at RT. H 2 O (100 ml) was added and resulting layers were separated. The aqueous layer was extracted with EtOAc (3x250 ml) and the combined organic layers were washed with brine (50 ml), dried over MgSO 4, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography (Petroleum Ether:EtOAc = 10:1->4:1->2:1) yielding the desired iodo-sulfone S-6 as a yellow oil (12.0 g, 70 % yield). TLC (Petroleum Ether:EtOAc = 2:1) 1 H-NMR (300 MHz, CDCl 3 ): = 2.47 (s, 2H, H-1), 7.59 (t, J = 7.5 Hz, 2 H), 7.43 (t, J = 7.2 Hz, 1H), 7.98 (d, J = 7.5 Hz, 2H) ; 13 C-NMR (75 MHz, CDCl 3 ): = 16.9 (C-1), 129.0, 129.4, 134.6, 135.9; IR (film): = 3016, 2948, 1583, 1477, 1446, 1369, 1307, 1211, 1157, 1134, 1080, 1024, 999, 931, 906, 844, 790, 769, 736, 707, 684, 671, 617; MS (APCI), m/z (%): 283 (100) [M + +H], 141 (7), 125 (12). 2-(((phenylsulfonyl)methyl)thio)benzo[d]thiazole (S-7) A solution of BT-SH (14.23 g, mmol, 1.0 equiv) in DMF (450 ml, 0.20M) was cooled to 0 C and NaH (60% in min. oil) (3.6 g, mmol, 1.05 equiv) was added portionwise within 10 min. The resulting solution was stirred at 0 C for 30 min, before ((iodomethyl)sulfonyl)benzene (S-6) (12.0 g, 42.5 mmol, 0.5 equiv) was added dropwise. The cooling bath was removed and the resulting mixture was stirred at 75 C for a further 18h. S-22

23 The resulting mixture was cooled to rt and saturated aqueous NH 4 Cl (200 ml) was added. Resulting layers were separated and the aqueous layer was extracted with EtOAc (3x400 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO 4, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography (Petroleum Ether:EtOAc = 10:1->4:1->2:1) yielding the desired sulfide-sulfone S-7 (8.3 g, 82 % yield) as yellowish crystals. TLC (Petroleum Ether:EtOAc = 2:1) Mp = C, lit. 17 = 144 C ; 1 H-NMR (300 MHz, CDCl 3 ): = 5.05 (s, 2H, H-1), (m, 5 H), 7.71 (t, J = 7.5 Hz, 2H), 7.97 (dd, J = 7.7 Hz, 1.6 Hz, 2H); 13 C-NMR (75 MHz, CDCl 3 ): = 54.9 (C-1), 121.1, 121.8, 124.9, 126.2, 128.7, 129.2, 134.0, 135.5, 137.0, 151.9, (C-2); IR (film): = 3060, 2995, 2916, 1583, 1446, 1427, 1307, 1238, 1207, 1149, 1124, 1081, 999, 829, 756, 727, 715, 688; MS (APCI), m/z (%): 322 (86) [M + +H], 292 (70), 167.(100) 2-(((phenylsulfonyl)methyl)sulfonyl)benzo[d]thiazole (12b) A solution of sulfone-sulfide S-7 (12.0 g, 37.3 mmol, 1.0 equiv) in EtOH (200 ml, 0.19M) was cooled to 0 C and (NH 4 ) 6 Mo 7 O 24.4H 2 O (4.6 g, 3.7 mmol, 0.1 equiv) was added. After 5 min at 0 C, 35% aqueous solution of H 2 O 2 (36.2 ml, mmol, 10.0 equiv) was added. The resulting mixture was stirred at 0 C for 30 min, before the cooling bath was removed and the stirring continued at RT for a further 18h. Saturated aqueous Na 2 S 2 O 3 (200 ml) was added and resulting layers were separated. The aqueous layer was extracted with EtOAc (3x250 ml) and the combined organic layers were washed with brine (150 ml), dried over MgSO 4, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography (Petroleum Ether:EtOAc = 4:1->2:1->1:1) yielding the desired bis-sulfone as yellowish crystals (10.26 g, 78 % yield) 18. S-23

24 TLC (Petroleum Ether:EtOAc = 2:1) Mp = 144 C 19 ; 1 H-NMR (300 MHz, CDCl 3 ): = 5.25 (s, 2H, H-1), (m, 2H), (m, 3H), (m, 3H), 8.21 (dd, J = 7.5, 1.6 Hz, 1H); 13 C-NMR (75 MHz, CDCl 3 ): = 72.5 (C-1), 122.6, 125.9, 128.1, 128.7, 129.3, 129.6, 135.2, 138.1, (C-2); IR (film): = 2952, 2896, 2844, 1583, 1552, 1467, 1448, 1419, 1330, 1315, 1217, 1164, 1145, 1080, 1026, 999, 854, 827, 759, 827, 759, 748, 729, 648, 617 ; MS (APCI), m/z (%): 322 (86) [M + +H], 292 (70), 167 (100). Characteristic peaks that belongs to sulfoxide-sulfone (S-8) by-product: 1 H-NMR (300 MHz, CDCl 3 J = 13.9 Hz, 1H, H-1), 4.98 (d, J = 13.9 Hz, 1H, H-1 ). S-24

25 Computations Computational details Geometry optimisation has been carried out using the Jaguar 7.5 pseudospectral program package. 20 These calculations used density functional theory (DFT) with the B3LYP functional 21 and the 6-31+G* basis set 22 on all atoms. All the optimization calculations were carried out using the Poisson-Boltzmann polarizable continuum method as incorporated in Jaguar, 23, and parameters for tetrahedron solvent (THF), i.e. a dielectric constant of 7.43, and a solvent probe radius of Å. Gas phase electronic energies were obtained by single point calculations at the SCS-MP2 level of theory 24 using ORCA program. 25 The ' aug-cc-pvtz' basis used is the standard aug-cc-pvtz basis 26 on all C, N, O and S atoms, the cc-(p)vtz basis on H atoms, and the G** basis 27 on lithium atom. Solvation energies were obtained by single point calculations using the Poisson-Boltzmann polarisable continuum method as implemented in Jaguar 7.5 program package, at the B3LYP/ccpVTZ level, using the parameters appropriate for THF. NBO analysis 28 has been performed at the B3LYP/cc-pVTZ level of theory using the Jaguar 7.5 program package. Reported charges are NPA charges. Conformational analysis Energies are given in kcal/mol relative to the most stable isomer. N S O S O R R = H, COMe, SO 2 Ph Li S-25

26 R = H Charge C1 = Charge C1 = Charge C1 = Charge C2 = Without Li + Charge C2 = Charge C2 = Charge C1 = Charge C2 = S-26

27 R = COMe Charge C1 = Charge C1 = Charge C1 = Charge C2 = Charge C2 = Charge C2 = Without Li Charge C1 = Charge C2 = Charge C1 = Charge C2 = S-27

28 R = SO 2 Ph Charge C1 = Charge C1 = Charge C1 = Charge C2 = Charge C2 = Charge C2 = Without Li Charge C1 = Charge C2 = Charge C1 = Charge C2 = S-28